Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor alpha (TNF alpha) has multiple biological functions including the prolonged activation of the collagenase and c-jun genes, which are regulated via their AP-1 binding sites. We show that incubating human fibroblasts with TNF alpha induces prolonged activation of JNK, the c-Jun kinase, which phosphorylates the transactivation domain of c-Jun. Furthermore, an immune complex kinase assay specifically demonstrates that TNF alpha stimulates the activity of JNK1, the recently described predominant form of JNK. TNF alpha also produces a small and transient increase in extracellular signal-regulated kinase (ERK) activity and no measured increase in Raf-1 kinase activity. On the other hand, epidermal growth factor causes a prolonged activation of Raf-1 kinase and ERK activity and a smaller, more transient activation of JNK, whereas the phorbol ester phorbol 12-myristate 13-acetate causes a small stimulation of Raf-1 kinase and a pronounced stimulation of ERK activity. The activation of JNK by TNF alpha does not correlate with Raf-1 or ERK activity. The kinetics of Raf-1, ERK, and JNK induction by epidermal growth factor, phorbol 12-myristate 13-acetate, or TNF alpha indicate distinct mechanisms of activation in human fibroblasts.
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PMID:Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. 792 60

Tumor necrosis factor alpha (TNF-alpha) has been shown to induce the production of interstitial collagenase by fibroblasts and chondrocytes. We investigated the role of TNF-alpha in collagenase gene expression by U937 monocyte/macrophage cells. Transcription of the TNF-alpha gene was observed after 0.5 h of phorbol myristate acetate (PMA) stimulation. Collagenase mRNA expression was not observed until 5-7 h of activation with PMA. TNF-alpha was detected in the culture supernatants 2-3 h before transcription of the collagenase gene. Neutralization of TNF-alpha protein with anti-TNF-alpha antibodies significantly reduced collagenase mRNA expression. Protein kinase C (PKC) and protein tyrosine kinase (PTK) inhibition essentially abolished both PMA-induced TNF-alpha protein secretion and collagenase mRNA expression. Collagenase gene expression induced by exogenous TNF-alpha in U937 cells stimulated with a suboptimal concentration of PMA was suppressed by PTK, but not PKC, inhibition. The pyrrolidine derivative of dithiocarbamate, a potent inhibitor of nuclear factor-kappa B (NF-kappa B) activation, resulted in a marked reduction in collagenase gene transcription, however, no reduction of TNF-alpha secretion was noted. Anti-TNF-alpha antibodies inhibited PMA-induced NF-kappa B activation. These observations demonstrate an important role for TNF-alpha in the autocrine regulation of collagenase gene expression by U937 cells. Additionally, TNF-alpha-induced PTK and NF-kappa B activation were important in collagenase gene expression in this cell line.
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PMID:Autocrine regulation of collagenase gene expression by TNF-alpha in U937 cells. 855 60

Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine that controls the initiation and progression of inflammatory diseases such as rheumatoid arthritis. Tpl2 is a MAPKKK in the MAPK (i.e. ERK) pathway, and the Tpl2-MEK-ERK signaling pathway is activated by the pro-inflammatory mediators TNFalpha, interleukin (IL)-1beta, and bacterial endotoxin (lipopolysaccharide (LPS)). Moreover, Tpl2 is required for TNFalpha expression. Thus, pharmacologic inhibition of Tpl2 should be a valid approach to therapeutic intervention in the pathogenesis of rheumatoid arthritis and other inflammatory diseases in humans. We have developed a series of highly selective and potent Tpl2 inhibitors, and in the present study we have used these inhibitors to demonstrate that the catalytic activity of Tpl2 is required for the LPS-induced activation of MEK and ERK in primary human monocytes. These inhibitors selectively target Tpl2 in these cells, and they block LPS- and IL-1beta-induced TNFalpha production in both primary human monocytes and human blood. In rheumatoid arthritis fibroblast-like synoviocytes these inhibitors block ERK activation, cyclooxygenase-2 expression, and the production of IL-6, IL-8, and prostaglandin E(2), and the matrix metalloproteinases MMP-1 and MMP-3. Taken together, our results show that inhibition of Tpl2 in primary human cell types can decrease the production of TNFalpha and other pro-inflammatory mediators during inflammatory events, and they further support the notion that Tpl2 is an appropriate therapeutic target for rheumatoid arthritis and other human inflammatory diseases.
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PMID:Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. 1784 81

Here, we describe optimal conditions for the culture of rainbow trout (Oncorhynchus mykiss) pre-adipocytes obtained from adipose tissue and their differentiation into mature adipocytes, in order to study the endocrine control of adipogenesis. Pre-adipocytes were isolated by collagenase digestion and cultured on laminin or 1% gelatin substrate. The expression of proliferating cell nuclear antigen was used as a marker of cell proliferation on various days of culture. Insulin growth factor-I stimulated cell proliferation especially on days 5 and 7 of culture. Tumor necrosis factor alpha (TNFalpha) slightly enhanced cell proliferation only at a low dose. We verified the differentiation of cells grown in specific medium into mature adipocytes by oil red O (ORO) staining. Quantification of ORO showed an increase in triglycerides throughout culture. Immunofluorescence staining of cells at day 11 revealed the expression of CCAAT/enhancer-binding protein and peroxisome proliferator-activator receptor gamma, suggesting that these transcriptional factors are involved in adipocyte differentiation in trout. We also examined the effect of TNFalpha on the differentiation of these adipocytes in primary culture. TNFalpha inhibited the differentiation of these cells, as indicated by a decrease in glycerol-3-phosphate dehydrogenase activity, an established marker of adipocyte differentiation. In conclusion, the culture system described here for trout pre-adipocytes is a powerful tool to study the endocrine regulation of adipogenesis in this species.
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PMID:Regulation of proliferation and differentiation of adipocyte precursor cells in rainbow trout (Oncorhynchus mykiss). 1857 24

Ethanol extract (RET) of Rosa multiflora Thunb flowers and its subfractions in ethylacetate (REA) or n-butanol subfractions (RBT) were reported to have potent antioxidative and anti-inflammatory activities. In this study, we investigated if those Rosa multiflora flower (RMF) extracts prevent ultraviolet (UV)-induced biochemical damages leading to photoaging. In keratinocyte or dermal fibroblasts, RET, REA, and RBT treatments with UV irradiation significantly decreased reactive oxygen species (ROS), interleukin (IL)-6, IL-8, and matrix metalloproteinase (MMP)-1 levels through suppression of nuclear factor kappa B and mitogen-activated protein kinases. In the animal experiment, mice were orally supplemented with RET (RET group) or REA and RBT mixture (RM group) for 10 weeks, concomitantly with UV exposure. Tumor necrosis factor alpha production and MMP-13 expression were reduced in the mouse skin of RET and RM groups compared with those in the UV control (UVC) group. UV-induced IL-6 production and epidermal thickening were reduced in RM group compared with those in UVC group. Eight phenolic compounds, including quercitrin (quercetin-3-O-rhamnoside), were identified in RMF extracts. Quercitrin treatment to dermal fibroblasts significantly attenuated an increase of MMP-1 expression and a decrease of type I procollagen expression caused by UV. Collectively, RMF extracts showed protective effects from UV-induced photoaging in the skin through suppression of ROS generation, proinflammatory cytokine production, and MMP expression. Quercitrin is suggested to be one of the effective compounds.
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PMID:Rosa multiflora Thunb Flower Extract Attenuates Ultraviolet-Induced Photoaging in Skin Cells and Hairless Mice. 3272 Dec 59